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transcription factors that dictate Th1 or Th2 function (T-bet
[7]
and GATA-3
[8]
, respectively) in the relative absence of effector cytokine secretion. Then,
with further maturation toward an “effector memory” (T
EM
) state, the Th1
subset realizes its potential for IL-2 and IFN-γ secretion, whereas the Th2
subset becomes a prolific secretor of IL-4, IL-5, IL-10, and IL-13. From a
bench-to-bedside perspective, it is critical to understand (as dissected later
in this chapter) that the relative state of polarized T cell differentiation is
a major determinant of the
in vivo
efficacy of adoptively transferred T-cell
populations.
And finally, we review the emerging theme of T-cell plasticity, as defined
by subset interconversion. Such plasticity has been particularly studied
and characterized with respect to the Treg subset, as: (1) Tregs can secrete
inflammatory cytokines upon loss of FOXP3 transcription factor
[9]
, (2)
individual Treg cells can coexpress FOXP3 and T-bet
[10]
, and (3) Treg cells
can convert to ROR-γ-expressing Th17 cells after IL-6-induced STAT3 acti-
vation
[11]
. Although it has been proposed that T-cell plasticity is particu-
larly prominent at the level of Treg/Th17 cell biology, it is possible that the
Th1 and Th2 phenotypes are also quite susceptible to subset interconver-
sion. For example, induction of dual Th1 and Th2 functionality has been
observed at the single-cell level
[12]
; and, in our own studies, we have found
that highly purified human Th1 cells are converted toward a Treg phenotype
through the effects of the Treg-associated molecule programmed death
ligand-1
[13]
. As such, polarization plasticity remains an important consid-
eration in attempts to control the Th1/Th2 post-transplant.
225
T-bet and Th1 differentiation: a deeper dive
Although T-bet represents a bona fide determinant and marker for Th1 cells,
T-bet is not cell-type specific, as it is expressed and plays an important role
in the biology of dendritic cells (particularly for the activation of antigen-
specific CD4
+
T cell responses
[14]
, CD8
+
T cells
[15]
, B cells (for regulation
of IgG class switching and production of pathogenic autoantibody
[16]
),
and natural killer (NK) cells (as a determinant of maturation and homeo-
stasis
[17]
)). And finally, T-bet can paradoxically contribute to the
in vivo
efficacy of CD4
+
Treg cells, perhaps by dictating a Treg cell migration pat-
tern toward inflammatory sites
[10]
; specifically, T-bet directs T-cell expres-
sion of the CXCR3 chemokine receptor and secretion of CCL3 (MIP-1α) and
CCL4 chemokines
[18]
. Of note, perhaps on the basis of this chemotactic
defect, T-bet-deficient Treg cells are unable to reverse the lethal inflamma-
tion in Treg-deficient scurfy mice
[18]
.
As such, T-bet is relatively ubiquitously expressed throughout the immune
system and does not always dictate a net increase in the host inflammatory
response. In light of this complex biology, it may be difficult to target T-bet
in a pharmacologic manner for specific modulation of a Th1-type response
after allogeneic HCT; in addition, successful targeting of transcription fac-
tors has been notoriously difficult. Nonetheless, modulation of T-bet levels
post-transplant may represent one molecular mechanism of action of cur-
rently utilized approaches to treat GVHD in the clinic, as T-bet levels are
reduced by glucocorticoids
[19]
and rapamycin
[20]
. As an alternative to
such pharmacologic approaches, we have hypothesized that allograft T-cell
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